Cancer is a major world-wide health problem. Given that the vast majority of human tumors are difficult to treat effectively, those afflicted suffer physically, emotionally and financially and inevitably die an early death. There is also a tremendous burden on the families and friends of those afflicted as well as on society at large. Accordingly, the ability to prevent cancer, delay its onset and/or slow its progression would benefit everyone.
Although extensive research around the world has led to advances in cancer treatment, progress has been slow and there is no known cure. However, modern molecular biological techniques have contributed to our understanding of the genetic aspects of cancer development. For example, the tumor suppressor gene p53, which is representative of a general class of genes that code for products that regulate cellular function by thwarting the cascade of events that causes a normally functioning cell to either die or become immortal, i.e., cancerous, has been shown to encode a transcription factor that suppresses tumor development. Mutations in the p53 tumor suppressor gene have been shown to affect the production of the oncogene-suppressing transcription factor. For example, either no transcription factor is produced or a transcription factor that is ineffectual or partially effective is produced. In fact, the p53 tumor suppressor gene is the most common site of genetic lesions in human cancers (Levine et al., Nature 351: 453–456 (1991); and Hollstein et al., Science 253: 49–53 (1991)), with more than half of all human tumors exhibiting p53 point mutations or deletions (Chang et al., Am. J. Gastroenterol. 88: 174–186 (1993)). Mutations in the p53 gene also have been associated with Li-Fraumeni syndrome, a familial autosomal dominant disease associated with an increased risk of tumorigenesis (Srivastava et al., Nature 348: 747–749 (1990)). The p53 protein also plays a role in the cellular response to DNA-damaging agents by facilitating in a block in the G1 phase of the cell cycle following DNA damage, thereby providing time for repair of the DNA damage (Pictenpol et al., Nature 365: 17–18 (1993); and Kuerbitz at al., PNAS USA 89: 7491–7495 (1992)) or by causing apoptosis (Yonish-Rouach et al., Nature 352: 345–347 (1991)).
In order to enable the further study of the p53 gene, recombinant DNA techniques have been used to develop rodent models. In one model, the rodents are homozygous for mutant p53 alleles (p53 −/−), such that the p53 gene is disrupted or “knock-out” (p53 −/−) and does not function, and the rodents are highly susceptible at an early age to a variety of tumors (Donehower et al., Nature 356; 251–221 (1992)). In another model, the rodents heterozygous for wild-type and mutant p53 alleles (p53 +/−) and, although they develop tumors 10–20 months after birth, they live considerably longer than the homozygous mutant p53 rodents (Harvey et al, Nature-Genetics 5: 225–229 (1993)). Exposure of these rodents to carcinogens, such as dimethylnitrosamine, or whole body irradiation accelerates tumor formation (Harvey et al. (1993), supra; and Lee et al., Oncogene 12: 3731–3736 (1994)).
Nitroxides are stable compounds, which are low in molecular weight, metal-independent, nontoxic and nonallergenic, and are characterized by low reactivity with oxygen, high solubility in aqueous solutions, and the ability to cross cellular membranes. The lipophilicity of nitroxides can be controlled by the addition of various organic substituents, in order to facilitate the targeting of the nitrides to specific organs or organelles.
Nitroxides have been shown to protect cells and animals against the untoward acute effects, such as cytotoxicity, of short-term exposure to lethal doses of free radicals and oxidative species, such as superoxide, hydrogen peroxide, hydroxyl radicals, and hydroperoxides, i.e., by functioning as antioxidants (U.S. Pat. No. 5,462,946). In cell culture, nitroxides have been shown to sensitize hypoxic cells to ionizing radiation and, paradoxically, protect aerobic cells from ionizing radiation. Also in cell culture, nitroxides have been shown to protect cells against the acute cytotoxic affects of paraquat and anti-neoplastic agents. Tempol, a nitroxide, has been shown to be cytotoxic against neoplastic cell lines in vitro (Monti et al., PAACR, 36: 387 (1995), and Monti et al., PAACR, 38: 193 (1997)). In animals, nitroxides have been shown to protect against radiation-induced alopecia and to induce weight loss. It has been reported that nitroxides can be used to protect against pulmonary adult respiratory distress syndrome, lenticular degeneration and hyaline membrane disease in infants, cataracts, oxidative stress, such as that associated with oxygen therapy or hyperbaric oxygen treatment, reperfusion injury, such as that associated with myocardial infarction, stroke, pancreatitis, intestinal ulceration, and organ transplantation.
It has now been surprisingly and unexpectedly discovered that nitroxides and prodrugs thereof are useful in the prophylactic and therapeutic treatment of cancer (i.e., prevention, delay of onset, and slowing of progression of cancer). Accordingly, it is an object of the present invention to provide a method for the prophylactic and therapeutic treatment of cancer. It is another object of the present invention to provide a composition for use in the method. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.